Learning from Patients: The Interplay between Clinical and Laboratory Research in AL Amyloidosis

Primary systemic light chain amyloidosis (AL) is a rare monoclonal plasma cell disorder. Much research has been performed to determine the factors that underly amyloidogenicity. However, there is increasing evidence that the primary clone, and also patient-related factors, influence the mechanism and rate of the process. The lessons learnt from patient care definitely imply that this is not solely due to the deposition of material in the tissues that cause organ injury but amyloid light chain precursors are likely to mediate cellular toxicity. The disease rarity, combined with the lack of in vitro tools, and that multi-organ failure has a wide clinical spectrum, result in investigative challenges and treatment limitations (due to AL patient frailty). All these characteristics make the disease difficult to diagnose and indicate the need to further study its origins and treatments. This review will focus on the various aspects of the amyloidogenic plasma cell clone, as learnt from the patient care and clinics, and its implications on basic as well as clinical trials of AL research. Details regarding the etiology of the plasma cell clone, understanding the diagnosis of AL, and improvement of patient care with specific consideration of the future perspectives of individualized patient therapy will be described.

Treatment in AL Amyloidosis: Moving towards Individualized and Clone-Directed Therapy

Systemic amyloid light chain (AL) amyloidosis is a rare protein deposition disease caused by a clonal B cell disorder of the bone marrow. The underlying diseases can be plasma cell disorders (monoclonal gammopathy of clinical significance, smoldering or symptomatic myeloma) or B cell non-Hodgkin’s lymphoma (e.g., Waldenstrom’s disease or marginal zone lymphoma) with secretory activity. It is crucial to characterize the underlying disease very precisely as the treatment of AL amyloidosis is directed against the (often small) B cell clone. Finally, the detection of cytogenetic aberrations of the plasma cell clone will likely play an important role for choosing an effective drug in the near future.

First report of CART treatment in AL amyloidosis and relapsed/refractory multiple myeloma

Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)–CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×106/kg BCMA–CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.

Left atrial strain in cardiac amyloidosis

Background Patients with cardiac amyloidosis (CA) display an enlarged and dysfunctional left atrium (LA), because of the effects of left ventricular (LV) diastolic and then systolic dysfunction, as well as the amyloid infiltration of LA wall. A single study reported impaired LA strain in CA, but differences among amyloid light-chain (AL) and transthyretin (ATTR) CA and the correlates of reduced LA strain have not been characterized. Methods We evaluated 426 consecutive patients undergoing a screening for suspected CA in 2 tertiary referral centres. Among them, 262 (61%) were diagnosed with CA (n=117 AL-CA, n=145 ATTR-CA). We measured peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) from 4- and 2-chamber (4C, 2C) views, and correlated them with maximum and minimum LA volumes, E/e' ratio, and LV global longitudinal strain (GLS). Results LA strain was much more severely impaired in patients with ATTR-CA than those without CA, and to a lesser extent than those with AL-CA (Figure). LA volumes were larger in patients with ATTR-CA than those without CA (maximal LA volume, p=0.042; minimal LA volume, p<0.001), and those with AL-CA (both volumes, p<0.001). LA strain values were more closely correlated with minimal than maximal LA volumes, and patients with AL-CA displayed stronger correlations than those with ATTR-CA or without CA; for example, Spearman's rho values for 4C-PALS vs. minimal LA volume were 0.595, 0.481, and 0.462, respectively (all p<0.001). Furthermore, LA strain correlated with E/e' in patients with AL-CA, but not in those with ATTR-CA: 4C-PALS vs. E/e', rho 0.406, p=0.001 (AL-CA), p=0.401 (ATTR-CA), and p=0.097 (no CA). Finally, LA strain correlated most closely with LV GLS in patients with AL-CA: 4C-PALS vs. LV GLS, rho 0.431, p<0.001 (AL-CA), rho 0.401, p<0.001 (ATTR-CA), rho 0.219, p=0.042 (no CA). Conclusions LA volume increase and reduced LA strain is particularly prominent in patients with ATTR-CA. Patients with AL-CA seem to display closer relationships between LA strain, size and haemodynamic load, possibly reflecting the most acute disease course, and lower time for amyloid deposition in the LA wall. FUNDunding Acknowledgement Type of funding sources: None.

Screening Tests for Early Diagnosis of Multiple Myeloma and Related Plasma Cell Disorders

Monoclonal gammopathy (MG) encompasses a diverse group of disorders characterized by the secretion of monoclonal immunoglobulins or their light-chain components. The incidence of multiple myeloma (MM) in South Korea is rapidly increasing, and it is important to be aware of its initial clinical presentations and the most efficient laboratory algorithms for early detection. Serum protein electrophoresis (SPE) and urine protein electrophoresis (UPE) are the primary screening tests for patients with clinically suspected MM or amyloid light-chain amyloidosis; these tests are reimbursed in South Korea. We reviewed clinical studies that applied national and international guidelines to evaluate test panels for early detection of MGs, including MM. The serum free light chain (sFLC) with SPE panel is recommended for the initial work up for diagnosis of MGs. In the case of a normal SPE, sFLC should be measured subsequently, so as not to miss the presence of M-protein. Use of this screening panel avoids medical expenses related to delayed diagnosis. Guidelines and recommendations suggest that no single method (SPE, serum immunofixation electrophoresis, sFLC, or UPE) should be used to exclude a diagnosis of MM. We believe that a screening test panel comprising SPE plus sFLC will increase the rate of early and accurate diagnosis of MM and related disorders.